The lifecycle of HIV-1 is intimately associated with membranes. The virus particles have a membrane envelope that contains structural proteins responsible for recognition and fusion with susceptible cells, and the final step of viral reproduction involves the budding out of new virus particles from the membrane of infected cells. Vpu is a small (81 residue) HIV-1 accessory protein with two biological functions. It enhances the degradation of CD4/gp160 complexes, enabling gp160 to be processed to form the gp41 and gp120 proteins required for the formation of new virus particles, and it facilitates the budding out of new virus particles, perhaps through its ion channel activity. Structural biology is based on the premise that in order to understand how proteins express their biological functions it is essential to determine their three-dimensional structures. And this is certainly the case for Vpu where its biological activities appear to be associated with different regions of the protein structure. However, membrane proteins like Vpu present extraordinary technical challenges for structural biology, largely because the most widely used experimental methods were developed for soluble, globular proteins rather than hydrophobic proteins in lipid environments. The goal of the proposed research is to determine the three-dimensional structure of Vpu by using newly developed NMR experimental methods. This will bring Vpu into the realm of structural biology, and make it feasible to work towards the additional goals of understanding the molecular mechanisms for its biological activities and designing drugs that interfere with these activities.